title: Fragment-based design of small molecule X-linked inhibitor of apoptosis protein inhibitors.
abstract: We report on a general structure- and NMR-based approach to derive druglike small molecule inhibitors of protein-protein interactions in a rapid and efficient manner. We demonstrate the utility of the approach by deriving novel and effective SMAC mimetics targeting the antiapoptotic protein X-linked inhibitor of apoptosis protein (XIAP). The XIAP baculovirus IAP repeat 3 (Bir3) domain binds directly to the N-terminal of caspase-9, thus inhibiting programmed cell death. It has been shown that in the cell this interaction can be displaced by the protein second mitochondrial activator of caspases (SMAC) and that its N-terminal tetrapeptide region (NH2-AVPI, Ala-Val-Pro-Ile) is responsible for this activity. However, because of their limited cell permeability, synthetic SMAC peptides are inefficient when tested in cultured cells, limiting their use as potential chemical tools or drug candidates against cancer cells. Hence, as an application, we report on the derivation of novel, selective, druglike, cell permeable SMAC mimics with cellular activity.
authors.affiliation: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Ziming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: Jason F
authors.initials: JF
authors.lastname: Cellitti
authors.forename: Xiyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Aras
authors.initials: A
authors.lastname: Emdadi
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases